Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Napimoga, Marcelo Henrique; Silva, Carlos A. T. da; Carregaro, Vanessa; Farnesi-de-Assunção, Thaís Soares; Duarte, Poliana Mendes; Melo, Nathalie Ferreira Silva de; Fraceto, Leonardo Fernandes

doi:10.4049/jimmunol.1200730

Cited by 49 publications

(89 citation statements)

References 47 publications

(57 reference statements)

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“…Linear regression resulted in correlation coefficient ( r ) values of 0.982, and release constant ( k ) values of 0.322 x 10 −2 (± 0.001) min -1 . Compared with the release profile of 15d-PGJ 2 from PLGA nanocapsules, the best fit was achieved using the Higuchi´s model ( r = 0.972; k = 0.048 min -1/2 ) and the main release mechanism involved is based on the Fick's Law of diffusion [16]. In this study, we achieved compatibility with the Baker–Lonsdale model indicating that the mechanism involved is also diffusion.…”

Section: Resultsmentioning

confidence: 60%

“…The concentration of the drug released was determined by HPLC in the acceptor compartment. The experiment was carried out in triplicate [16,24]. …”

Section: Methodsmentioning

confidence: 99%

“…In order to increase the bioaviability and improve the pharmacological properties of 15d-PGJ 2 , our group demonstrated that PLGA-encapsulated 15d-PGJ 2 achieved the same therapeutic effect as free 15d- PGJ 2 in several inflammation models at a concentration 33 times lower than the latter [15]. Encapsulated 15d-PGJ 2 was also able to inhibit bone loss in periodontal disease secondary to reduced gingival inflammation [16]. Such findings highlight the promising applications of 15d- PGJ 2 encapsulated in nanoparticles.…”

Section: Introductionmentioning

confidence: 99%

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15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation

et al. 2016

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15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2.

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Section: Resultsmentioning

confidence: 60%

“…The concentration of the drug released was determined by HPLC in the acceptor compartment. The experiment was carried out in triplicate [16,24]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation

et al. 2016

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“…For example, 15d-PGJ 2 was detected in the exosomal preparations derived from RBL-2H3 cells [22]. 15d-PGJ 2 demonstrated potent anti-inflammatory properties in different experimental models [23]. These studies suggest that transport of phospholipases and lipid mediators to the site of inflammation may represent another mechanism for anti-inflammatory action of exosomes.…”

Section: Discussionmentioning

confidence: 96%

Exosomes from Human Dental Pulp Stem Cells Suppress Carrageenan-Induced Acute Inflammation in Mice

et al. 2015

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The primary goal of this study was to examine the effects of human dental pulp stem cell-derived exosomes on the carrageenan-induced acute inflammation in mice. Exosomes were purified by differential ultracentrifugation from the supernatants of stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) cultivated in serum-free medium. At 1 h post-carrageenan injection, exosomes derived from supernatants of 2 × 10(6) SHEDs were administered by intraplantar injection to BALB/c mice; 30 mg/kg of prednisolone and phosphate-buffered saline (PBS) were used as positive and negative controls, respectively. Edema was measured at 6, 24, and 48 h after carrageenan injection. For the in vivo imaging experiments, AngioSPARK750, Cat B 750 FAST, and MMPSense 750 FAST were administered into the mouse tail vein 2 h post-carrageenan injection. Fluorescence images were acquired at 6, 24, and 48 h after edema induction by IVIS Spectrum in vivo imaging system. Exosomes significantly reduced the carrageenan-induced edema at all the time points studied (by 39.5, 41.6, and 25.6% at 6, 24, and 48 h after injection, respectively), to similar levels seen with the positive control (prednisolone). In vivo imaging experiments revealed that, both exosomes and prednisolone suppress activities of cathepsin B and matrix metalloproteinases (MMPs) at the site of carrageenan-induced acute inflammation, showing more prominent effects of prednisolone at the early stages, while exosomes exerted their suppressive effects gradually and at later time points. Our study demonstrates for the first time that exosomes derived from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice.

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“…Knowing that both induced actions are the result of drug action on different subcellular locations, we hypothesized that it is possible to control such biphasic pharmacodynamics by utilizing a drug delivery system. 15d-PGJ2 has been formulated in many nanoparticle platforms, including PLGA nanocapsules, 19 liposomes, 20 and albumin conjugates, 21 to enhance its pharmacokinetics and tissue targeting. A nanoemulsion (NE) is also a widely used carrier for lipophilic drugs, since this formulation enhances their solubility, pharmacokinetics, and tissue targeting by utilizing both passive and active targeting.…”

mentioning

confidence: 99%

Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

Abbasi¹,

Kajimoto²,

Harashima³

2016

IJN

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15-Deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (> 83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level

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Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Cited by 49 publications

References 47 publications

15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation

15d-PGJ2-Loaded Solid Lipid Nanoparticles: Physicochemical Characterization and Evaluation of Pharmacological Effects on Inflammation

Exosomes from Human Dental Pulp Stem Cells Suppress Carrageenan-Induced Acute Inflammation in Mice

Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

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